Elsevier

Brain Research

Volume 908, Issue 1, 10 July 2001, Pages 86-92
Brain Research

Research report
Conditioned fear stimuli reinstate cocaine-induced conditioned place preference

https://doi.org/10.1016/S0006-8993(01)02638-5Get rights and content

Abstract

These studies examined the ability of a conditioned stimulus previously paired with footshock to reinstate cocaine-induced conditioned place preference. Male rats were given either odor or tone in a paired (PRD group) or explicitly unpaired (random, RND group) manner with footshock. All rats were subsequently trained in a cocaine conditioned place preference (CPP) task. Cocaine CPP was demonstrated in all groups. After CPP extinction, presentation of the conditioned fear stimulus produced a greater degree of reinstatement in PRD rats compared to the RND group. This was true whether the conditioned stimulus was odor or tone, but when odor was used as the conditioned stimulus, the RND group also partially reinstated cocaine CPP. In rats trained with tone as the conditioned stimulus, presentation of the tone during the test for reinstatement produced robust reinstatement of cocaine CPP only in the PRD, but not RND, group. In contrast, a subsequent priming injection with cocaine reinstated cocaine CPP equally in both RND and PRD groups. These studies indicate for the first time that conditioned fear stimuli induce reinstatement of cocaine CPP, and suggest that stimuli associated with prior stress may produce relapse in humans.

Introduction

One of the most troubling aspects of cocaine dependence in humans is the craving and relapse that occur for many years. Potentially important contributors to relapse are stressful life events. Several studies have reported that individuals exposed to higher levels of stress are more likely to undergo relapse to alcohol and other drugs [11], [17], [25].

The mechanism by which stress leads to reinstatement (relapse) of drug-seeking and drug-taking behavior remains to be elucidated. However, more recently, animal models of drug dependence have used self-administration and conditioned place preference procedures to examine the role of stress in reinstatement of drug-seeking behavior. Stewart and Shaham and coworkers (see [23] for review), as well as others, have demonstrated through extensive and elegant studies that stress produces robust reinstatement of cocaine [1], [6], heroin [21], nicotine [22] and alcohol [12] self-administration. Nearly all studies have used footshock stress as the stimulus to reinstate drug-seeking (lever-pressing) in animals previously extinguished for this behavior. Two recent reports using the conditioned place preference (CPP) procedure have also demonstrated that footshock reinstates morphine-induced place preference [14], [27].

The self-administration studies mentioned above demonstrated that a footshock stress produced clear reinstatement of lever pressing, but that a conditioned fear stress or a predatory odor presentation did not reinstate drug self-administration (see [23]). One possibility for differences in the ability to induce reinstatement by these stimuli is that activation of nociceptive pathways by footshock may be involved in producing the reinstatement. This does not seem likely, however, given that food-deprivation also induces reinstatement of drug self-administration [5], [24]. An alternative possibility is that, since conditioned fear behavior is manifest as an increase in freezing behavior in the rat, this response may interfere with the ability to lever-press on a test for reinstatement.

The present study examined whether a conditioned fear stress would reinstate cocaine conditioned place preference. Such findings may be of consequence to humans because they would suggest that stimuli previously associated with stressful events could precipitate relapse. For the studies described herein, it was reasoned that approach to the drug-paired chamber would be minimally impaired by a conditioned fear stimulus, as compared to active lever-pressing required in self-administration studies. Pilot studies in this laboratory indicated that a conditioned fear stimulus produced significant reinstatement of cocaine CPP in rats previously given the conditioned stimulus paired with footshock (PRD group). However, no comparison was conducted in rats given random presentations of footshock with the conditioned stimulus (RND group). Here we repeated the studies in the PRD group of rats and included a RND group to determine whether the ability of the conditioned fear stimulus would reinstate cocaine CPP to a greater extent in the PRD vs. RND group.

Section snippets

Materials and methods

Experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and experimental protocols were approved by the University Animal Care and Use Committee. Male Sprague–Dawley rats weighing 260–280 g were supplied by Simonsen Laboratories (Gilroy, CA, USA). Rats were housed with food and water available ad libitum in constant temperature and humidity conditions on a 12 h light–dark cycle (light period 07.00 to 19.00 h).

The box used for

Results

The results in Fig. 1A–C show conditioned place preference behavior in RND and PRD groups trained and tested for reinstatement by the conditioned odor. Both groups demonstrated a significant place preference for the cocaine-paired side on the Cocaine Test (compared to day 0; P<0.0001 for both groups using a paired t-test). Fig. 1A shows that during extinction, rats did not reach the values for time spent on the cocaine-paired side as low as those demonstrated on day 0, the preconditioning day.

Discussion

These findings indicate that a conditioned odor or tone that has been previously paired with a footshock elicits reinstatement of cocaine CPP. Presentation of tone provided a robust stimulus for the reinstatement of cocaine CPP, in which rats spent nearly all of the 15 min test period in the cocaine-paired compartment, despite the observation that the freezing response declined after the first 5 min.

These results are in general agreement with several studies by Stewart and Shaham and coworkers

Acknowledgements

This work was supported by US Public Health Service grant DA 11787 (BAS).

References (27)

  • R.J. Frohardt et al.

    The effects of neurotoxic hippocampal lesions on two effects of context after fear extinction

    Behav. Neurosci.

    (2000)
  • S.E. Hemby et al.

    Conditioned locomotor activity but not conditioned place preference following intra-accumbens infusions of cocaine

    Psychopharmacology

    (1992)
  • T.R. Kosten et al.

    A 2.5-year follow-up of depressions, life crises, and treatment effects on abstinence among opioid addicts

    Arch. Gen. Psychiatry

    (1986)
  • Cited by (0)

    View full text